Adrenaline (also known as epinephrine) is a hormone and a neurotransmitter. Adrenaline has many functions in the body, such as regulating heart rate, blood pressure and air passage diameters, and metabolic shifts, such as energy metabolism. Release of adrenaline is a crucial component of the fight-or-flight response of the sympathetic nervous system.
Adrenaline, (−)-3,4-dihydroxy-[(methylamino)methyl]benzyl alcohol, is a member of a group of monoamines called the catecholamines. It is produced in some neurons of the central nervous system, and in the chromaffin cells of the adrenal medulla from the amino acids phenylalanine and tyrosine.
Adrenaline is available in a variety of formulations suited for different clinical indications and routes of administration, for example by injection, by inhalation, or by topical use. Its uses include combating low blood pressure during hemorrhagic or allergic shock; opening the airways during asthmatic attack; restricting the distribution of locally administered drugs such as local anesthetics; reducing nasal congestion; and/or performance aid in emergency situations. The hydrochloride, sulphate, and bitartrate salts are known to be used in pharmaceutical compositions.
Adrenaline may also be used to stimulate or improve the coagulation competence in a subject to control bleeding disorders that have several causes such as clotting factor deficiencies (e.g. hemophilia A and B or deficiency of coagulation Factors XI or VII) or clotting factor inhibitors and also to control excessive bleeding occurring in subjects with a normally functioning blood clotting cascade (no clotting factor deficiencies or inhibitors against any of the coagulation factors). Such bleeding may, for example, be caused by a defective platelet function, thrombocytopenia or von Willebrand's disease.
Bleeding is also a major problem in connection with surgery and other forms of tissue damage.
Adrenaline oxidizes easily and darkens slowly on exposure to air and therefore instability of current adrenaline formulations constitute a major problem during storage if this issue is not properly addressed.
Today, dilute solutions are partially stabilized by the addition of chlorobutanol and by reducing agents, such as sodium bisulfite or ascorbic acid. Unfortunately, allergic reactions to the bisulfite preservatives are often observed, such that formulations containing bisulfites will be contraindicated in individuals having such allergies. Adrenaline contains an amine group and therefore it forms salts with acids including the hydrochloride, the borate, and the bitartrate. The bitartrate has the advantage of being less acidic and is used in the eye because its solutions have a pH close to that of lacrimal fluid. Adrenaline is destroyed readily in alkaline solutions by aldehydes, weak oxidizing agents and oxygen of the air. Other disadvantages of adrenaline include a short duration of action, decomposition of its salts in solution, vasoconstriction action frequently followed by vasodilation and inactivity on oral administration.
Instability has also been observed when drugs are combined with adrenaline. For example, when lidocaine hydrochloride is mixed with adrenaline hydrochloride the buffering capacity of the lidocaine raises the pH of the intravenous admixtures above 5.5, the maximum necessary for stability of the adrenaline, to about 6. Under these conditions, the adrenaline hydrochloride will begin to deteriorate within several hours.
US patent application no. US 2008/0269347 describes an epinephrine formulation that has enhanced stability. In particular the formulations disclosed in this document are injectable formulations. The formulations comprise epinephrine, EDTA and one or more antioxidant such as cysteine, citric acid, acetylcystein or thioglycerol. The formulations are suitable for any medical condition that is in need of epinephrine, such as anaphylaxis, asthma or cardiac arrest. The formulations disclosed in this document comprises about 1 mg/ml epinephrine.
US patent application no. US 2012/0029085 also relates to stabilization of compositions, which contain catecholamine drugs, such as for example epinephrine.
The stability of these compositions is achieved through the inclusion of an appropriately selected pH buffer and a thiol agent, based on redox and pH buffering principles including pKa of the buffer and of the reversibly protonated amine group. In this document the stabilized pharmaceutical injection solutions comprise 1 mg/ml epinephrine.
Pharmaceutical compositions on the market today typically contain a high concentration of adrenaline in order to fulfil the requirements with regard to stability. These compositions must be diluted before they can be administered to the subject in need thereof. The consequence for not using diluted compositions may be detrimental, and the subject's life may be lost. In case of emergencies valuable time may be wasted performing this act of dilution. Moreover, the dilution act may induce a risk of contamination, especially if the medicament must be administered in the field, such as for example at a car crash.
Clearly there remains a need to develop pharmaceutical injection solutions that are prepared and stored as ready for use medicaments and which fulfils the requirements with regard to stability during periods of storage.